The term "controlled release" refers generally to techniques for administering an agent wherein the agent is released in a certain manner affecting either the location or the timing of the release. Controlled release techniques have particular advantages in the context of administering therapeutic agents. For example, the release rate of a drug can be predicted and designed for an extended duration; this eliminates problems associated with patients neglecting to take required medication in specified dosages at specified times. Many drugs have short half-lives in the body before being removed. Trapping these drugs in polymeric matrices increases the time in which the drug maintains its activity. Further, the site specific localization of a drug achieved with a targeted delivery technique reduces or eliminates systemic side effects that certain medications cause when administered orally or intravenously.
There are several general types of controlled release systems. For example, drug release can be diffusion controlled, meaning that the diffusion of the agent trapped within a polymer matrix is the rate-determining factor for the overall release rate. Erosion based systems also exist in which a polymer degrades over time and releases a drug in an amount proportional to the gradual erosion. An osmotic pumping device uses osmotic pressure as the driving force for release. A fourth system is based on the swelling of a polymeric matrix, such as a hydrogel. Hydrogels are polymers that absorb and swell in an aqueous environment. The release of the agent is dependent on the volume increase of the gel upon swelling and is then diffusion controlled.
One mechanism which utilizes swelling for controlled release involves the movement of a solvent into a polymer matrix. The solvent must be thermodynamically compatible with the polymer. The solvent moves toward the core of the matrix at a constant velocity, which is a factor in determining the release rate of the solute drug (Ritger and Peppas, 1987). The penetration of the matrix creates stresses between polymer chains. In order to accommodate these stresses, the chains respond by moving and increasing their end-to-end distance. This response causes a lowering of the polymer's glass transition temperature (T.sub.g), and mesh size (free volume between the chains) increases to swell the polymer. The increased mesh and increased mobility of the chains in the swollen region result in increased permeability of the polymer to the solvent (Korsmeyer and Peppas, 1984). In pH sensitive polymers, the pH of the environment influences the release rate of the solute by affecting the swelling behavior of the gel (Brannon-Peppas and Peppas, 1989).
One context in which the use of controlled release systems has been investigated involves the treatment of urinary tract infections associated with ureteral catheters or stent. The ureter functions as a pathway for urine leading from the kidney to the bladder. Obstruction of the ureter requires the placement of a ureteral stent to open the pathway and assist in the passage of urine or the passage of the cause of the obstruction, such as kidney stones. The ureteral stent functions by dilating the ureter to allow urine to flow and may also act as a guide for urine within the ureter, using the holes located along the length of the catheter or stent.
Although stenting is an effective technique for aiding in the passage of both urine and stones, the presence of the device in the ureter can cause complications. According to Kunin, 40% of all hospital-associated(nosocomial) infections are related to the urinary tract (Kunin, 1987). Of these urinary tract infections, 80% are a consequence of catheterization (Fowler, 1989). After only one week of indwelling catheterization, the risk of infection is about 50%. Such catheterization is used in about 20% of patients in chronic care facilities such as nursing homes. More than 50% of these patients experience encrustation and blockage of their catheters, which inhibits the flow of urine. Inhibited flow can lead to a host of more serious problems for the patient if not corrected.
There are at least three possible mechanisms by which a catheterized ureteral area becomes infected. Bacteria can be introduced during the insertion of the stent, or the organisms can enter the urinary tract through the urethral meatus and subsequently migrate along the stent. The third possibility is that the bacteria utilize their ability to rise within a volume of fluid. The bacteria can actually migrate up the urinary tract via the urine (Franco et al., 1990). Once the bacteria have been introduced and colonize an area it takes only 24-48 hours for a relatively low concentration of bacteria (10.sup.2 -10.sup.4 /ml) to grow into a clinically significant population (.gtoreq.10.sup.5 /ml) (Stamm, 1991).
Once established, the bacteria migrate along the catheter aided by the formation of biofilms (Nickel et al., 1992). Biofilms are aggregations of microorganisms surrounded by an extracellular matrix of exopolysaccharide (Swartz et al., 1991). The bacteria are sandwiched between this polysaccharide coat and the catheter. Therefore, the bacteria are isolated and separated from the surrounding ureteral environment. This isolation can lead to complications in executing an effective therapy against the bacteria due to their protection within the biofilm (McLean et al., 1991).
Certain species of bacteria such as the Gram-negative microbe Proteus mirabilis secrete the enzyme urease that degrades urea in the urine to form carbon dioxide and ammonia. The presence of ammonia increases the pH of the urine leading to the precipitation of magnesium ammonium phosphate salts and certain calcium phosphate salts. Struvite, hydroxyapatite, and carbonate apatite account for 10-20% of urinary encrustations (Olson et al., 1989). Although this fraction is small, the presence of these encrustations is considered a more significant risk to health than the presence of other stones because of their high growth rates.
Catheters dipped and coated in antibiotic solutions have been produced to address the problem of infections developing with ureteral catheterization. See, for example, Izumi et al., EP 0 065 884; Whitbourne et al., EP 0 426 486; and Soloman, U.S. Pat. No. 4,999,210. Prophylactic use of antibiotics to control the bacteria that cause these encrustations, however, has proved unsatisfactory. Despite use of antibiotics, such as ciprofloxacin, given systemically, bacteria grow and multiply within the biofilm slime layer on urinary catheters. Continuous use or release (Reid et al., 1993; Soloman and Shevertz, 1987) of antibiotics in the absence of infection is of debatable merit because of drug side effects and the possibility of producing resistant strains.
Prevention of encrustation can be achieved by using a urease inhibitor to prevent the degradation of urea. The urease inhibitor competes with urea for active sites on the urease molecule. Various chemicals have been studied for their effect on the activity of urease and the crystallization of struvite (ammonium magnesium phosphate). Chondroitin sulfate and heparin sulfate have proven ineffective in preventing struvite encrustation. Sodium citrate shows potential; however, the mechanism of control does not involve the actual inhibition of urease but involves a possible complexation of the Mg++ ions (McLean et al., 1990). Silver is used as a surface modification for preventing catheter bacteriuria (Liedberg et al., 1990).
Acetohydroxamic acid (AHA) is another option for prevention of urease-associated encrustation. It inhibits urease in a manner similar to boric acid (Breitenbach and Hausinger, 1988). Acetohydroxamic acid has been shown to be rapidly metabolized with a half-life of approximately five to ten hours (Takeuchi et al., 1980).
In selecting a stent or catheter, certain characteristics are desirable. The material should not prompt an immune response. The tube should also be flexible enough to avoid discomfort to the patient during catheterization but stiff enough to allow easy insertion. The polymer composing the stent should be sterilizable and should maintain its mechanical properties throughout the duration of implantation (Brazzini et at, 1987; Mardis, 1987). Common ureteral stent materials include: C-FLEX (styrene-ethylene/butylene block copolymer modified with polysiloxane); polyurethane; silicone; and SILITEK.
Hydrogels are polymers which absorb water and swell in aqueous environments. Hydrogels are usually polymerized from a hydrophilic water-soluble monomer such as acrylic acid and crosslinked to yield a network polymer. When water is absorbed, the crosslinks prevent the polymer from dissolving, and the polymer swells (Tarcha, 1991).
Hydrogels have been used for many medical applications including contact lenses and surgical drainage tubes (Lee, 1988; Pearce et al., 1984). Hydrogels have also been used for coating urinary catheters or have actually been formed in the shape of a tube for use as a catheter (Ramsay et al., 1986) Upon swelling, the hydrogel's coefficient of friction is reduced, and the polymer becomes slippery. This property makes insertion and removal of the catheter less traumatic and reduces the inflammatory response of the urothelial tissue. Controlled release of active agents, such as antibiotics, from hydrogels is another application that is advancing rapidly (Soloman and Sheretz, 1987).